To understand the mechanism of the vascular leak syndrome (VLS) caused by interleukin-2, we examined light and electron microscopic alterations in lung, liver, spleen, kidney and heart of mice in which an early stage of the VLS was produced by the administration of interleukin-2 over 4 days. These studies disclosed considerable damage to endothelial cells especially in venules and small veins of lung and liver. In addition, there were frequent sites of transendothelial passage of lymphoid cells, probably lymphokine-activated killer cells, which penetrated through their cytoplasm by means of "temporary migration pores" and accumulated in the perivascular spaces. Our studies indicate that a direct in vivo interaction between activated lymphocytes and endothelium results in cytotoxicity to endothelial cells.